Villous Architecture in Colorectal Adenomas: Molecular Pathogenesis, Epithelial Plasticity, and Malignant Risk

Villous morphology is routinely used to stratify risk in conventional colorectal adenomas, yet it remains largely interpreted as a visual histological descriptor. This review proposes a different view: villous architecture is a graded, spatially organized epithelial state that links premalignant tissue remodeling to malignant potential. Across histological, molecular, and microenvironmental studies, villous-containing adenomas show convergent features of WNT-driven stem-like expansion, YAP-associated plasticity, fetal-regenerative or fetal-metaplastic transcriptional programs, mucin remodeling, stromal activation, immune attenuation, and genomic instability. These features appear to arise through interacting routes rather than through a single deterministic mutation. This framework helps explain why villous proportion predicts risk imperfectly: it captures a composite biological state but does not resolve its individual components. Quantitative morphometry, spatial transcriptomics, multiplex imaging, and region-resolved genomics could therefore move villous architecture from an observer-dependent category to a continuous, biologically interpretable marker of early malignant transition. Such a shift may improve adenoma classification, refine surveillance strategies, and identify high-risk lesions before conventional thresholds for advanced histology are reached.